Research Interests

Protein synthesis in mammalian mitochondria

The role of mitochondria in aging, heart disease, diabetes, neurodegenerative disorders, obesity, and cancer is becoming more apparent due to their central role in energy metabolism. In mammals, mitochondria are responsible for providing over 90% of the energy in the form of ATP, which is generated by the process of oxidative phosphorylation (Figure). Mitochondria have their own 16.5 kb circular genome and translation machinery/ribosomes essential for the synthesis of 13 essential proteins of the oxidative phosphorylation (OXPHOS) complexes (Figure). Mammalian mitochondrial ribosome (55S) is composed of ~80 mitochondrial ribosomal proteins (MRPs), about half of which have homologs in bacterial ribosomes. Although many of the maternally-inherited mitochondrial disorders result from mutations in mitochondrial DNA, alterations in expression levels and mutations of MRPs also affect mitochondrial protein synthesis and cell growth. Indeed, there is growing evidence suggesting the involvement of MRPs in various disease states, apoptosis and cancer. Clearly, changes in the expression of MRPs influence mitochondrial metabolism and alter the balance between apoptosis and tumor formation due to the changes in energy production.

Our laboratory has paved the way to study mitochondrial translation by identifying all the protein components of the ribosome and translation initiation factor 3 (mtIF3) in mammalian mitochondria. Recently, we revealed the modification of MRPs by phosphorylation and acetylation at steady-state levels using mass spectrometry-based proteomics. Based on these observations, we postulated that the mitochondrial translation machinery is regulated by post-translational modifications (PTMs) as NAD+ and ATP levels regulate the activities of many other mitochondrial enzymes involved in oxidative phosphorylation (Figure). The location of the phosphorylated ribosomal proteins mainly at the functional regions such as the mRNA- and tRNA-binding paths and L7/L12 stalk of the ribosome is particularly exciting and suggest important functional roles for these modifications in the regulation of translation. Kinase(s) responsible for phosphorylation of the MRPs is currently under investigation in our laboratory.

Another novel regulatory mechanism we discovered is the regulation of mitochondrial protein synthesis by reversible acetylation of a ribosomal protein, MRPL10. We have also shown the deacetylation of MRPL10 by a ribosome associated deacetylase, SIRT3, in an NAD+-dependent manner. A member of the sirtuin family of NAD+-dependent deacetylases, SIRT3, is located in mammalian mitochondria and is important for the regulation of mitochondrial metabolism, cell survival and longevity. Thus, specific deacetylation of MRPL10 by SIRT3 may play a pivotal role in coordinating the activity of the mitochondrial protein synthesis machinery with the [NADH]/[NAD+] ratio and regulate oxidative phosphorylation in mammalian mitochondria (Figure).

Our current research interests are all integrative and aimed at determining how components of mitochondrial translation/ribosomes affect the oxidative phosphorylation and apoptosis in normal and disease conditions. As we learn more about the regulatory roles of MRPs and their PTMs, new strategies will be devised to manipulate mitochondrial function/dysfunction in metabolic diseases, cancer, and aging. Our multidisciplinary research takes advantage of biochemical, molecular and cell biological, and mass spectrometry-based proteomics technologies in a “systems biology” approach.

HUNTINGTON, W.Va. — Dr. Anita Aperia, professor of pediatrics at Karolinska Institutet in Stockholm and former member of the Nobel Assembly, who is widely recognized for her groundbreaking research to medicine’s understanding of how the ‪‎kidneys function in health and disease, … Continue reading →

HUNTINGTON, W.Va. – One of the world’s leading kidney authorities and researchers will be speaking next week at Marshall University. Dr. Anita Aperia, professor of pediatrics at Karolinska Institutet in Stockholm and a former member of the Nobel Assembly, is … Continue reading →

Miranda Carper, Ph.D., a December 2014 graduate of Marshall University’s Joan C. Edwards School of Medicine Biomedical Sciences Ph.D. program, had her manuscript published in Genes and Cancer, a leading journal in the field. Dr. Carper worked in the lab … Continue reading →

HUNTINGTON, W.Va.—Maria A. Serrat, Ph.D, assistant professor in the department of anatomy and pathology at the Marshall University Joan C. Edwards School of Medicine, and a team of multidisciplinary researchers from several institutions have received federal grant funds totaling $383,000 … Continue reading →

Tenacious. Passionate. Driven. These are the words that Sean Piwarski uses to describe himself. Piwarski is this year’s recipient of the Chancellor’s Scholarship, given to a student in Marshall University’s Joan C. Edwards School of Medicine Biomedical Sciences Ph.D. Program. … Continue reading →

Dr. Richard Egleton’s (Neuroscience and Developmental Biology Cluster Coordinator) manuscript, Drug Abuse and the Neurovascular Unit, was included in the prestigious journal, Advances in Pharmacology (71: 451-480, 2014). Published on August 22, the article focuses on the role of the … Continue reading →

HUNTINGTON, W.Va. – Dr. Gary Rankin with the Marshall University Joan C. Edwards School of Medicine and co-investigators at institutions around West Virginia, including West Virginia University, have received a five-year renewal grant from the National Institutes of Health (NIH) … Continue reading →

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